Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice
Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca2+-dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might be involved in the pathogenesis of POCD.
In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.
Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment.
Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.
KeywordsSurgery Cognitive dysfunction Neuroinflammatioin NMDAR Calpain BDNF TrkB
Brain-derived neurotrophic factor
Bovine serum albumin
An intracellular domain
Nonsteroidal anti-inflammatory drugs
Perioperative neurocognitive disorders
Postoperative cognitive decline
Calpain-specific spectrin breakdown products
Tumor necrosis factor-α
New truncated TrkB
Truncated isoforms of TrkB
Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients after anesthesia and surgery, especially in the elderly . POCD receives increasing attention because it negatively affects cognitive domains such as memory, attention, and concentration, which are associated with a prolonged hospitalization, a reduced quality of life, and an increased morbidity and mortality [2, 3]. However, its pathophysiology remains unknown.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the central nervous system, which plays a critical role in neuronal survival and differentiation, and synaptic plasticity through activation of its full-length receptor (TrkB-FL) [4, 5]. Dysregulation of BDNF/TrkB signaling contributes to many pathological processes, including traumatic brain injury [6, 7], brain ischemia [8, 9], and neurodegenerative diseases [10, 11]. However, truncated isoforms of TrkB receptors (TrkB-TC) act as negative modulators of TrkB-FL receptors [12, 13], and alterations in TrkB-TC:TrkB-FL ratio are thought to cause and/or reflect dysregulation of BDNF/TrkB signaling [8, 14]. In an in vitro study, excitotoxic stimulation of cultured rat hippocampal neurons with glutamate downregulated TrkB-FL while upregulated TrkB-TC receptors, which results in dysregulation of BDNF/TrkB signaling . In our previous study, we have showed that decreased expression of BDNF is involved in the pathogenesis of POCD . However, whether TrkB-TC also plays a mechanistic role in POCD remains unclear.
Calpains are intracellular Ca2+-dependent cysteine proteases that play a physiologic role by the cleavage of several substrates, including the neurotrophin receptor TrkB , cytoskeletal proteins, and membrane receptors . A calpain-dependent truncated form of TrkB-FL has been reported to participate in neurodegenerative diseases, such as AD  and epilepsy . The overactivation of calpain could lead to changes in hippocampal structure and function  and also be linked to neuronal death . Calpain is overactivated by increased Ca2+ concentrations and one source of intracellular Ca2+ is NMDARs related. Importantly, one recent study showed that amyloid-β peptide (Aβ) induced the overactivation of NMDARs and calpain, and then triggered the formation of a truncated isoform (TrkB-T′) and an intracellular domain (ICD) fragment, and ultimately disrupted BDNF/TrkB signaling, which can be prevented by a NMDAR antagonist memantine . However, it remains unclear whether the overactivation of NMDARs and a calpain-dependent truncated form of TrkB-FL is involved in the development of POCD.
Inflammation has been proved to be a potential source of reactive oxygen species for inducing NMDARs hypofunction and nonsteroidal anti-inflammatory drugs (NSAIDs) can improve impaired NMDAR-dependent synaptic plasticity and age-related cognitive dysfunction . In addition, accumulating evidence suggests that neuroinflammation plays an initial and central role in anesthesia and surgery-induced cognitive impairments [15, 22, 23]. Upon all these points, we hypothesized that anesthesia and surgery-induced neuroinflammation overactivated NMDARs, and the abnormal activation of NMDARs triggered the overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice.
Materials and methods
Exploratory laparotomy was performed under isoflurane anesthesia described as our previous studies [15, 23]. Mice were anesthetized in an anesthesia chamber prefilled with 1.5% isoflurane in oxygen. The surgery was performed immediately after 30 min exposure to isoflurane. An abdominal median incision approximately 1 cm was made to allow penetrating the peritoneal cavity. Then the viscera, intestine, and musculature were explored by the operator. Sterile 4-0 chromic gut sutures were used to suture the peritoneal lining and skin. In order to prevent infection, the wound was dressed with polysporin (Pfizer, USA). The surgical procedure was also under isoflurane anesthesia and lasted for 10 min. For the mice that served as controls, neither anesthesia nor surgery was performed.
The NMDAR antagonist memantine (MEM, 20 mg/kg, Sigma, St Louise, MO, USA)  was intraperitoneally (i.p.) administered to the mice before anesthesia and then once daily for subsequent 5 consecutive days. The calpain inhibitor, MDL-28170 (20 mg/kg, Sigma, St Louise, MO, USA) , was administered to the mice by i.p. before anesthesia and then once daily for the subsequent 5 consecutive days. The selected doses are based on previous studies demonstrating memantine and MDL-28170 confers neuroprotective effects [24, 25].
A white opaque plastic chamber (40 cm × 40 cm × 40 cm, XR-XZ301, Shanghai Softmaze Information Technology Co., Ltd., Shanghai, China) was used as the open-field arena. The open-field test was performed at 5 days post-surgery to assess the exploratory locomotor activity. Each mouse was placed in the center of the arena and left to explore it for 5 min while activity was automatically recorded by a video tracking system.
The Y maze is a symmetrical three-arm maze (XR-XY1032; Shanghai Softmaze Information Technology Co., Ltd., Shanghai, China) and is used to evaluate the spontaneous alternation performance at 6 days post-surgery. Each mouse was placed in the center of the Y maze and could explore freely throughout the three different arms of the maze during an 8-min session. The sequence and total number of arms entered were recorded. Arm entry was complete when the hind paws of the mouse had been completely placed in the arm. The alteration was determined from successive consecutive entries to the three different arms on overlapping triads in which all arms were represented. For example, a sequence of entries to the three arms ABC, ACBABACABA, would generate four “successful” alternations, ACB, CBA, BAC, and CAB. Percentage alternation is the number of triads containing entries into all three arms divided by the maximum possible alternations (the total number of arms entered minus 2) × 100. The re-entry into the same arm was not counted for analysis .
Mice were trained for fear conditioning at 7 days post-surgery. Each mouse was placed into a conditioning chamber (XR-XC404; Shanghai Softmaze Information Technology Co., Ltd., Shanghai, China) and allowed to explore freely for 3 min. Then a 30-s tone (70 db, 3 kHz) was delivered followed by a 2-s foot shock (0.7 mA). After that, the mouse stayed in the chamber for another 30 s and then returned to the home cage. Contextual fear conditioning (a hippocampus-dependent task) was assessed 24 h after training. For the contextual fear conditioning, each mouse was placed back into the same chamber in which they were explored for 5 min without tone or foot shock and scored for the freezing behavior. Freezing behavior was defined as the absence of all visible movement except for respiration. Given that no difference was observed in the auditory-cued fear test (a hippocampus-independent task) between control and surgery group in our previous studies [15, 23], the test was not performed in the present study.
The entire dissected hippocampus was harvested and subjected to Western blot analysis. The samples were lysed as described previously [15, 23]. Protein concentration was determined by BCA protein assay kit (Beyotime, China). Equivalent amounts of proteins per lane were separated on SDS-PAGE gels and then transferred to polyvinylidinene fluoride (PVDF) membranes. Membranes were blocked with 5% skimmed milk in Tris-buffered saline with Tween (TBST) for 1 h at room temperature. And then the membranes were incubated at 4 °C overnight with primary antibodies including rabbit anti-IL-1β (1:500; Abcam, Cambridge, UK), rabbit anti-IL-6 (1:1000; Affinity, Cincinnati, USA), rabbit anti-TNF-α (1:500, Cell Signaling Technology, Danvers, MA, USA), rabbit anti-GluN2A (1:1000; Abcam, Cambridge, UK), rabbit anti-GluN2B (1:1000; Abcam, Cambridge, UK), mouse anti-αIIspectrin (1:200; Santa Cruz Biotechnology, Dallas, TX, USA), mouse anti-BDNF (1:500; Abcam, Cambridge, UK), mouse anti-TrkB (1:300; Santa Cruz Biotechnology, Dallas, TX, USA), rabbit anti-bax (1:200; Santa Cruz Biotechnology, Dallas, TX, USA), mouse anti-bcl-2 (1:300; Santa Cruz Biotechnology, Dallas, TX, USA), rabbit anti-caspase3 (1:1000; Cell Signaling Technology, Danvers, MA, USA), mouse anti-GAPDH (1:5000; ProteinTech group, Chicago, USA), and rabbit anti-β-tubulin (1:3000; ProteinTech group, Chicago, USA). After washing in TBST three times, the membranes were incubated for 1 h at room temperature with goat anti-rabbit and goat anti-mouse IgG-horseradish peroxidase-conjugated secondary antibodies (1:7000, Bioworld Technology, St. Louis Park, MN, USA). The protein bands were detected by enhanced chemiluminescence, exposed onto X-ray film, and quantitated with Image J software (National Institutes of Health, Bethesda, MD, USA).
Mice were deeply anesthetized with 2% sodium pentobarbital in saline (60 mg/kg, i.p.; Sigma, St Louise, MO, USA) and transcardially perfused with saline, followed by 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS; pH 7.4). Brains were removed and postfixed in 4% PFA for 2 h and dehydrated in 30% sucrose at 4 °C overnight and then embedded in O.C.T. compound. The brains were cut coronally into 10-μm-thick sections from bregma − 1.70 to − 2.30 by a freezing microtome and mounted on glass slides. The sections were blocked with 1% bovine serum albumin (BSA) for 1 h at room temperature. And then the sections were incubated with primary antibodies: rabbit anti-Iba1 (1:500, Wako Pure Chemical Industries, Osaka, Japan) and rabbit anti-GFAP (1:1000, Sigma, St Louise, MO, USA) in 1% BSA at 4 °C overnight. Sections were washed with PBS three times and incubated with goat anti-rabbit IgG-FITC (1:600; Bioworld Technology, St. Louis Park, MN, USA) and goat anti-rabbit IgG-Cy3 (1:600; Bioworld Technology, St. Louis Park, MN, USA) for 1 h at room temperature. After washing out the secondary antibodies, sections were incubated with 4′,6-diamidino-2-pheny-lindole (DAPI) for nuclear staining. Fluorescent images were captured by a confocal microscope (Olympus, FV1000, Japan). Six sections of the hippocampus per mouse were analyzed by ImageJ (National Institutes of Health, Bethesda, MD, USA) for immunofluorescence analysis. Three non-overlapping fields of each section in the hippocampal Cornu Ammonis 1 (CA1) area was randomly acquired by a counting frame size of 0.4 mm2. Positively stained areas were defined that the number of pixels per image with intensity in which was above a predetermined threshold level. The immunoreactivity of a protein was quantified by percentage area with positive staining to the total area of the imaged field. All quantitative analyses were performed by an experimenter blinded to the group of each sample.
The brains of mice were processed at 8 days post-surgery for Golgi-Cox staining  using a Golgi Stain Kit (#PK401, FD NeuroTechnologies, Columbia, MD, USA). Briefly, mice were deeply anesthetized by sodium pentobarbital in saline (60 mg/kg, i.p.; Sigma, St Louise, MO, USA) and rapidly sacrificed. The brains were removed as quickly as possible; rinsed in double-distilled water; immersed in impregnation solution, which was a mixture of solutions A and B; and stored in the dark at room temperature (22–25 °C) for 3 weeks. Next, the brains were transferred into solution C and stored for 7 days. Finally, the brains were sliced at a thickness of 100 μm with oscillating tissue slicers, stained and then mounted on gelatin-coated slides. After alcohol dehydration, the tissue sections were cleared in xylene and coverslipped. The hippocampal neurons were captured by an EVOS FL auto microscope (Life technology) under Z-stack mode (× 20 object) for dendritic analysis. The dendrites from hippocampal neurons in CA1 region were captured with a confocal microscope (× 100 oil objective). Dendrite branches were traced by the NeuronJ plugin in ImageJ software, and the dendritic length was calculated. Sholl analysis was applied to measure the dendritic intersections in concentric circles per 20 μm from the cell soma. Dendritic spine density was detected along CA1 secondary dendrites starting from their point of origin on the primary dendrite, and the counting was performed by an experimenter blinded to the group of each sample.
Statistical analyses were analyzed by the GraphPad Prism version 8.0 statistical package (Graphpad Software, Inc.). Data are presented as mean ± S.E.M. Differences between groups were assessed with one-way ANOVA followed by post hoc Tukey multiple comparisons. The dendritic intersections were analyzed by repeated-measures ANOVA followed by post hoc Tukey multiple comparisons. A significant difference was considered as p < 0.05.
Inhibition of NMDAR attenuated the activation of microglia and astrocytes and proinflammatory cytokines after anesthesia and surgery
Inhibition of NMDAR limited the activation of calpain and TrkB-FL cleavage after anesthesia and surgery
Inhibition of NMDAR or calpain reversed BDNF/TrkB signaling disruption and decreased apoptosis after anesthesia and surgery
Inhibition of NMDAR or calpain attenuated anesthesia and surgery-induced hippocampal dendritic spine loss
Inhibition of NMDAR or calpain attenuated cognitive impairments after anesthesia and surgery
Patients suffering from cognitive impairments after anesthesia and surgery have been recognized for more than 60 years. Recently, a multi-specialty working group recommended “perioperative neurocognitive disorders” (PND) as an overarching term for cognitive impairments diagnosed in the preoperative or postoperative period [28, 29, 30, 31, 32, 33]. PND includes cognitive decline diagnosed before operation (described as neurocognitive disorder), postoperative delirium (POD), delayed neurocognitive recovery, and POCD. Since we focused on cognitive performance during the postoperative period, we still used the term of POCD in the current study.
Although various mechanisms have been proposed to be involved in the development of POCD, neuroinflammation is believed to play an initial and central role. In the present study, we showed that IL-1β and IL-6 levels were significantly increased and lasted for 8 days post-surgery. Our results were consistent with the previous studies [15, 22, 34], suggesting that the hippocampus is susceptible to neuroinflammation induced by anesthesia and surgery. However, the mechanism by which neuroinflammation leading to cognitive impairments following anesthesia and surgery remains unclear.
There is accumulating evidence suggesting a strong correlation between neuroinflammation and NMDAR dysfunction, eventually resulting in deficits of synaptic plasticity and cognitive impairments. It has been showed that microglia is activated initially and become a major cellular source of a variety of proinflammatory cytokines in a rat model of chronic neuroinflammation, which has negative effect on long-term potentiation requiring NMDAR activation . In addition, the anti-inflammatory agent indomethacin has been reported to improve cognitive impairments by inhibiting microglia activation and reversing NMDAR dysfunction in aged rats . On the other hand, another study has showed that NMDA-induced retinal excitotoxicity could trigger microglia recruitment and IL-1β production . In our study, we found that anesthesia and surgery induced neuroinflammation and NMDAR overactivation. Although we do not know which signaling works as an initial trigger, we speculate there is a possible cross-talk between neuroinflammation and NMDAR overactivation, leading to cognitive impairments in aging mice.
We previously demonstrated that NMDARs calcium/calmodulin-dependent kinase II pathway was involved in the pathogenesis of POCD . Therefore, the present study tested the hypothesis that NMDARs may be implicated in the overactivation of calpain in POCD. NMDARs are ligand-gated ion channels, which have tetrameric structure composed of GluN1, GluN2A-D, and GluN3A-B subunits, forming di- or triheteromers with participation of GluN1. The most widely expressed NMDARs contain the obligatory subunit GluN1 plus either GluN2A or GluN2B or a mixture of the two. In particular, NR2B is involved in NMDA-mediated excitotoxicity , while NR2A is associated with human immunodeficiency virus-mediated neurotoxicity . Here, we showed the levels of GluN2A and GluN2B were significantly increased after anesthesia and surgery. The treatment of memantine, a low-affinity uncompetitive NMDAR antagonist without affecting normal physiological activity, attenuated anesthesia and surgery-induced overactivation of NMDARs and calpain and improved cognitive impairments in aging mice. It has been previously demonstrated that memantine is neuroprotective in various brain diseases, including AD , Parkinson’s disease , traumatic brain injury , and pain-induced cognitive impairments , which involves its anti-inflammation, anti-oxidation, anti-apoptosis, and anti-glutamate excitotoxicity properties. In our study, we showed that NMDAR/Ca2+/calpain is mechanistically involved in neuroprotective effects of memantine in anesthesia and surgery-induced cognitive impairments in aging mice. In a rat model of postoperative pain-induced cognitive impairments, memantine treatment could improve memory deficits without any effect on NMDAR expression . Interestingly, we showed that memantine downregulated the levels of GluN2A and GluN2B. Indeed, one previous study suggests that memantine inhibited ethanol-induced upregulation of NMDA receptor subunits GluN2A and GluN2B in rat hippocampal neurons . Thus, this downregulation of GluN2A and GluN2B levels by memantine seems to be responsible for its neuroprotective effects in aging mice after anesthesia and surgery.
BDNF plays an important role in neuronal plasticity, learning, and memory through the activation of TrkB-FL receptors [4, 5]. It has been reported that reduced BDNF signaling through TrkB-FL leads to impaired memory [45, 46]. IL-1β has been shown to negatively regulate BDNF-dependent learning and memory in neurodegenerative diseases . In our previous study, we demonstrated that anesthesia and surgery could induce microglial activation, I L-1β release, and BDNF downregulation in the hippocampus and thus resulted in hippocampus-dependent cognitive impairments in aged mice . In support, we showed that microglia and astrocyte-induced neuroinflammation plays a crucial role in the development of POCD. Moreover, alteration in BDNF signaling can result in synaptic dysfunction that is associated with memory deficits observed in AD , Parkinson’s disease (PD) , stroke , and sepsis-associated encephalopathy . In the present study, we showed that anesthesia and surgery induced decreased levels of BDNF, which could be reversed by memantine and MDL-28170. The results are consistent with a previous study in PD animal model . Therefore, we speculate that neuroinflammation and overactivated calcium signaling pathway may contribute to the downregulation of BDNF levels after anesthesia and surgery in aging mice. However, it remains unclear whether the alteration of TrkB is involved in the development of POCD.
TrkB is expressed as a full-length, catalytically active isoform (TrkB-FL), as well as several alternatively spliced truncated isoforms lacking the intracellular kinase domain, including TrkB.T1, TrkB.T2, and TrkB.T-Shc [51, 52]. Both TrkB-FL and TrkB-TC are widely expressed throughout the adult mammalian CNS . Abnormal levels of TrkB-TC have been reported in several neurodegenerative disorders, such as AD , Down syndrome , and amyotrophic lateral sclerosis . It has been reported that overexpression of TrkB-FL improves spatial memory in mice , whereas overexpression of TrkB.T1 slightly impairs it . In a mouse model of Down syndrome, the accelerated death of hippocampal neurons is not rescued by exogenous BDNF delivery  but instead by restoring the physiological levels of TrkB.T1 . In a mouse model of spinal cord injury, the increased levels of TrkB.T1 contribute to locomotor dysfunction and neuropathic pain . In the present study, we showed that expression of TrkB-FL was significantly decreased after anesthesia and surgery, whereas TrkB-ICD was significantly increased. Increasing evidence has showed that excitotoxicity is associated with the downregulation of TrkB-FL and upregulation of TrkB-TC expression . The abnormal activation of calpain has been shown to associate with excitotoxicity and mediates neuronal injury by cleavage on TrkB-FL receptor in stroke and ischemic neurodegeneration . It has also been demonstrated that Aβ induced a calpain-mediated cleavage on TrkB-FL receptors, producing a new truncated TrkB receptor (TrkB-T′) and a 32-kDa intracellular fragment (TrkB-ICD), which was also detected in postmortem human brain samples . Besides, the overactivation of calpain has been associated with several neuropsychiatric disorders, including Huntington’s disease , Parkinson’s disease , and brain trauma . In our study, anesthesia and surgery induced overactivation of calpain and subsequently resulted in increased TrkB-ICD and decreased TrkB-FL levels, which were rescued by calpain inhibitor MDL-28170. This suggests that the strategy targeting at calpain is a promising therapeutic strategy for cognitive impairment after anesthesia and surgery.
There are some limitations in this study. Firstly, we mainly observed relatively short-term cognitive performance by Y maze and fear conditioning tests after anesthesia and surgery. Using Morris water maze to measure spatial cognition are needed in our future studies. Secondly, memantine is a partial antagonist of NMDAR receptor that block the pathological activation of NMDARs, while not interfering with normal synaptic transmission . Clinically, memantine is a commercially available and FDA-approved drug used for the treatment of AD patients. That is the reason why we did not use the selective GluN2A and GluN2B subunit antagonists in this study. In addition, we only detected a 32-kDa intracellular fragment (TrkB-ICD), but not new truncated TrkB receptor, which deserves further study in the future.
In summary, our study demonstrated that neuroinflammation overactivated NMDARs, at least in part, plays a key role in overactivation of calpain, cleavage of TrkB-FL receptor, BDNF/TrkB signaling dysfunction, dendritic spine loss, cell apoptosis, and consequent cognitive impairments. Hence, identifying viable therapeutic strategies to tackle abnormal activation of NMDARs or calpain may provide effective interventions for POCD.
We thank Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging for technical support and Jiangsu Key Laboratory of Developmental Genes and Human Diseases for providing the confocal microscope.
LLQ and WP carried out the Western blotting analysis and drafted the manuscript. DL and XYS performed behavioral tests. GFZ performed the immunofluorescence. ZQZ performed statistical analysis. JJY and MHJ designed the study and helped to draft the manuscript. All authors read and approved the final manuscript.
This work was supported by the grants from the National Natural Science Foundation of China (Nos., 81600950, 81971892) and by the Fundamental Research Funds for the Central Universities (Number 2242017 K41013).
Ethics approval and consent to participate
The Ethics Committee of Zhongda Hospital, Medical School, Southeast University, approved all animal experiments described in this study.
Consent for publication
The authors declare that they have no competing interests.
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